Prenatal sodium channel dysfunction in Dravet syndrome alters cortical development

Neurodevelopmental disorders associated with epilepsy are typically linked to postnatal dysfunction of synaptic proteins and ion channels, yet increasing evidence suggests a role for these proteins before birth. The voltage-gated sodium channel Nav1.1, encoded by SCN1A , is well studied postnatally. SCN1A mutations result in a broad range of neurological phenotypes including developmental and epileptic encephalopathies (DEEs including Dravet syndrome, DS) and fetal lethality. Here, we investigated the role of SCN1A dysfunction in early corticogenesis. By integrating data from DS patient-derived forebrain models, a DS mouse model, and DS post-mortem tissue, we report altered G2/M cell cycle transition, with a shift towards earlier neurogenic fate commitment. These changes lead to altered cortical specification at birth and throughout life. The early developmental roles of Nav1.1 complement the well-known postnatal roles in neuronal excitability. These discoveries reveal new insights into the DS pathogenesis and a new non-canonical role for Nav1.1 in early corticogenesis.